期刊
NEUROSCIENCE
卷 332, 期 -, 页码 191-202出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2016.07.003
关键词
iron-overload; iron chelator; combined therapy; dendritic spine; mitochondrial dynamic
资金
- Thailand Research Fund, Thailand [BRG5780016, TRG5880045]
- Royal Golden Jubilee program, Thailand [PHD/0222/2557]
- NSTDA Research Chair Grant from the National Science and Technology Development Agency, Thailand
- Chiang Mai University Center of Excellence Award, Thailand
Iron-overload can cause cognitive impairment due to blood-brain barrier (BBB) breakdown and brain mitochondrial dysfunction. Although deferiprone (DFP) has been shown to exert neuroprotection, the head-to-head comparison among iron chelators used clinically on brain iron overload has not been investigated. Moreover, since antioxidant has been shown to be beneficial in iron overload condition, its combined effect with iron chelator has not been tested. Therefore, the hypothesis is that all chelators provide neuroprotection under iron-overload condition, and that a combination of an iron chelator with an antioxidant has greater efficacy than monotherapy. Male Wistar rats (n = 42) were assigned to receive a normal diet (ND) or a high-iron diet (HFe) for 4 months. At the 2nd month, HFe-fed rats were treated with a vehicle, deferoxamine (DFO), DFP, deferasirox (DFX), n-acetyl cysteine (NAC) or a combination of DFP with NAC, while ND-fed rats received vehicle. At the end of the experiment, rats were decapitated and brains were removed to determine brain iron level and deposition, brain mitochondrial function, BBB protein expression, brain mitochondrial dynamic, brain apoptosis, tau-hyperphosphorylation, amyloid-beta (A beta) accumulation and dendritic spine density. The results showed that iron-overload induced BBB breakdown, brain iron accumulation, brain mitochondrial dysfunction, impaired brain mitochondria! dynamics, tau-hyperphosphorylation, A beta accumulation and dendritic spine reduction. All treatments, except DFX, attenuated these impairments. Moreover, combined therapy provided a greater efficacy than monotherapy. These findings suggested that iron-overload induced brain iron toxicity and a combination of an iron chelator with an antioxidant provided a greatest efficacy for neuroprotection than monotherapy. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
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